The use of oncolytic bacteria, or compositions of oncolytic bacterias, for combatting neoplasms in humans and animals is known. For example EP 564 121, GB 1,587,244 and U.S. Pat. No. 3,192,116 disclose the use of non-pathogenic bacteria that result in the liquification and lysis of tumours in vertebrates. However in many instances, for example with the use of Clostridium, the tumours are only partially destroyed, and tumour regrowth may still occur. To ensure control of tumour growth the administration of bacteria, followed by chemotherapeutic drugs, for example 5-fluorodeoxyuridine or alkylating agents, has been suggested (e.g. GB 1,069,144).
Several viruses have also been shown to exhibit tumoricidal properties, for example parvovirus H-1 (Dupressoir et al., 1996. Cancer Res, 49:3203-3208), Newcastle disease virus (Reichand et al., 1992. J. Surg. Res, 52:448-453) or retroviral vectors containing drug susceptibility genes (Takamiya et al., 1993. J. Neurosurg, 79:104-110). WO97/26904 and WO96/03997 disclose a mutant herpes simplex virus (HSV-1761) that inhibits tumour cell growth. Administration of HSV-1716 comprising a 759 base pair deletion in each copy of γ34.5 of the long repeat region (RL) to tumour cells kills these cells. However, this virus is specific for neuronal cells as HSV is known to selectively inhabit the neuronal system. Furthermore, the use of common human pathogens as an oncolytic virus is limited as it is likely that the general population has been infected and acquired an immune response to such viruses. A preexisting immune response to a viral strain similar to the one used as a therapeutic agent in the treatment of a cancer may attenuate the effectiveness of the virus as therapeutic agent.
Other virus strains have reported oncolytic activity. The ONYX-015 human adenovirus (produced by ONYX pharmaceuticals) is believed to replicate preferentially in p53 negative tumour cells. This virus shows promise in clinical trials with head and neck cancer patients (Kirn, D., T. et al., Nat Med, 1998. 4:1341-1342). Reovirus type 3 is being developed by Oncolytic Biotech as a cancer therapeutic, which preferentially grows in PKR −/− cells (Yin, H. S., J Virol Methods, 1997. 67:93-101; Strong, J. E. and P. W. Lee, J Virol, 1996. 70:612-616; Strong, J. E., et al., Virology, 1993. 197:405-411; Minuk, G. Y., et al., J Hepatol, 1987. 5:8-13; Rozee, K. R., et al., Appl Environ Microbiol, 1978. 35:297-300). Reovirus, type III exhibited enhanced replication properties in cells which expressed the mutant ras oncogene (Coffey, M. C., et al., Science, 1998. 282:1332-1334; Strong, J. E., et al., Embo J, 1998. 17:3351-1362). Mundschau and Faller (Mundschau, L. J. and D. V. Faller, J Biol Chem, 1992. 267:23092-23098) have shown that the ras oncogene product activated an inhibitor of PKR, and this coupled with the observation that the PKR chemical inhibitor 2-aminopurine increased the growth of Reo type III in normal cells implicates PKR is a critical regulator of the growth of reovirus.
WO 99/04026 teaches the use of VSV as a vector in gene therapy for the expression of a wide range of products including antibodies, immunogens, toxins, etc. for the treatment of a variety of disease disorders.
Interferons are circulating factors which bind to cell surface receptors activating a signalling cascade ultimately leading to a number of biological responses. Two of the outcomes of interferon signalling are tightly linked: (1) an antiviral response and (2) induction of growth inhibitory and/or apoptotic signals.
U.S. Pat. No. 4,806,347 discloses the use of γ Interferon and a fragment of INF-γ (known asΔ4α2) against human tumour cells.
WO 99/18799 reports the cytotoxic activity of Newcastle Disease Virus (NDV) and Sindbis virus towards several human cancer cells. However, both viruses demonstrated selectivity in their cytotoxic activity towards tumor cells.
WO 99/18799 discloses that interferon addition to normal cells renders these cells resistant to NDV, yet, this effect was not observed with interferon-treated tumor cells which continued to exhibit NDV-induced sensitivity. WO 99/18799 also discloses the cytotoxic activity of VSV cells against KB cells (head and neck carcinoma) and HT 1080 (Fibrosarcoma), and alleviation of cytotoxicity in normal and tumor cells, by VSV, in the presence of interferon. No other cell types were tested against VSV cytotoxic activity.
Certain mutant strains of VSV have been reported. Stanners, et al., Virology (1987) 160 (1):255-8. Francoeur, et al., Virology (1987) 160 (1):236-45. Stanners, et al., J. Gen. Virol. (1975) 29 (3):281-96. Stanners, et al., Cell (1977) 11 (2):273-81.
The present invention relates to viral formulations that are useful in the treatment of diseases and cancers, preferably leukaemia. Such formulations may also comprise an oncolytic VSV strain and a chemical agent, for example a cytokine which confers to normal cells, resistance to viral infection, but leaves diseased or cancerous cells susceptible to viral infection and lysis.
It is an object of the invention to overcome disadvantages of the prior art.
The above object is met by the combinations of features of the main claims, the sub-claims disclose further advantageous embodiments of the invention.